BACKGROUND/ OBJECTIVE: Hypomagnesemia (Hypo-Mg) in rodents leads to neurogenic inflammation associated with substance P (SP) elevations; neutral endopeptidase (NEP) is a principle cell surface proteolytic enzyme, which degrades SP. The effects of chronic Hypo-Mg on neutrophil NEP activity, cell activation and the associated cardiac dysfunction were examined. METHODS/ RESULTS: Male Sprague-Dawley rats (180 g) were fed Mg-sufficient or Mg-deficient (Hypo-Mg) diets for five weeks. Enriched blood neutrophils were isolated at the end of one, three and five weeks by step gradient centrifugation. NEP enzymatic activity decreased by 20% (P value was nonsignificant), 50% (P<0.025) and 57% (P<0.01), respectively, for week 1, 3 and 5 Hypo-Mg rats. In association, neutrophil basal superoxide (•O(2) (-))-generating activities were elevated: 30% at week 1 (P value was nonsignificant), and fourfold to sevenfold for weeks 3 to 5 (P<0.01). Maximal phorbol myristate acetate-stimulated •O(2) (-) production by Hypo-Mg neutrophils increased twofold at week 5. Also, plasma 8-isoprostane levels were elevated twofold to threefold, and red blood cell glutathione decreased by 50% (P<0.01) after three to five weeks of chronic Hypo-Mg. When Hypo-Mg rats were treated with the SP receptor blocker (L-703,606), neutrophil NEP activities were retained at 75% (week 3) and 77% (week 5) (P<0.05); activation of neutrophil •O(2) (-) and other oxidative indexes were also significantly (P<0.05) attenuated. After five weeks, histochemical (hematoxylin and eosin) staining of Hypo-Mg-treated rat ventricles revealed significant white blood cell infiltration, which was substantially reduced by L-703,606. Echocardiography after three weeks of Hypo-Mg only showed modest diastolic impairment, but five weeks resulted in significant (P<0.05) depression in both left ventricular systolic and diastolic functions; changes in these functional parameters were attenuated by L-703,606. CONCLUSION: NEP activity regulates neutrophil •O(2) (-) formation by controlling SP bioavailability. When oxidative inactivation of NEP is prevented by SP receptor blockade, partial protection is afforded against cardiac contractile dysfunction.
BACKGROUND/ OBJECTIVE:Hypomagnesemia (Hypo-Mg) in rodents leads to neurogenic inflammation associated with substance P (SP) elevations; neutral endopeptidase (NEP) is a principle cell surface proteolytic enzyme, which degrades SP. The effects of chronic Hypo-Mg on neutrophil NEP activity, cell activation and the associated cardiac dysfunction were examined. METHODS/ RESULTS: Male Sprague-Dawley rats (180 g) were fed Mg-sufficient or Mg-deficient (Hypo-Mg) diets for five weeks. Enriched blood neutrophils were isolated at the end of one, three and five weeks by step gradient centrifugation. NEP enzymatic activity decreased by 20% (P value was nonsignificant), 50% (P<0.025) and 57% (P<0.01), respectively, for week 1, 3 and 5 Hypo-Mg rats. In association, neutrophil basal superoxide (•O(2) (-))-generating activities were elevated: 30% at week 1 (P value was nonsignificant), and fourfold to sevenfold for weeks 3 to 5 (P<0.01). Maximal phorbol myristate acetate-stimulated •O(2) (-) production by Hypo-Mg neutrophils increased twofold at week 5. Also, plasma 8-isoprostane levels were elevated twofold to threefold, and red blood cell glutathione decreased by 50% (P<0.01) after three to five weeks of chronic Hypo-Mg. When Hypo-Mg rats were treated with the SP receptor blocker (L-703,606), neutrophil NEP activities were retained at 75% (week 3) and 77% (week 5) (P<0.05); activation of neutrophil •O(2) (-) and other oxidative indexes were also significantly (P<0.05) attenuated. After five weeks, histochemical (hematoxylin and eosin) staining of Hypo-Mg-treated rat ventricles revealed significant white blood cell infiltration, which was substantially reduced by L-703,606. Echocardiography after three weeks of Hypo-Mg only showed modest diastolic impairment, but five weeks resulted in significant (P<0.05) depression in both left ventricular systolic and diastolic functions; changes in these functional parameters were attenuated by L-703,606. CONCLUSION:NEP activity regulates neutrophil •O(2) (-) formation by controlling SP bioavailability. When oxidative inactivation of NEP is prevented by SP receptor blockade, partial protection is afforded against cardiac contractile dysfunction.
Authors: W B Weglicki; I T Mak; J H Kramer; B F Dickens; M M Cassidy; R E Stafford; T M Philips Journal: Cardiovasc Res Date: 1996-05 Impact factor: 10.787
Authors: Jay H Kramer; Christopher Spurney; Micaela Iantorno; Constantine Tziros; I-Tong Mak; M Isabel Tejero-Taldo; Joanna J Chmielinska; Andrei M Komarov; William B Weglicki Journal: Am J Med Sci Date: 2009-07 Impact factor: 2.378
Authors: Maria Isabel Tejero-Taldo; Jay Harlan Kramer; Iu Tong Mak; Andrei M Komarov; William Bernard Weglicki Journal: Heart Fail Rev Date: 2006-03 Impact factor: 4.654
Authors: William B Weglicki; Jay H Kramer; Christopher F Spurney; Joanna J Chmielinska; I Tong Mak Journal: Can J Physiol Pharmacol Date: 2012-05-30 Impact factor: 2.273
Authors: Shaiban Jubair; Jianping Li; Heather M Dehlin; Edward J Manteufel; Paul H Goldspink; Scott P Levick; Joseph S Janicki Journal: Am J Physiol Heart Circ Physiol Date: 2015-06-12 Impact factor: 4.733
Authors: Joanna J Chmielinska; Jay H Kramer; I-Tong Mak; Christopher F Spurney; William B Weglicki Journal: Mol Cell Biochem Date: 2019-12-18 Impact factor: 3.396
Authors: I Tong Mak; Jay H Kramer; Joanna J Chmielinska; Christopher F Spurney; William B Weglicki Journal: J Cardiovasc Pharmacol Date: 2015-01 Impact factor: 3.105
Authors: I Tong Mak; Jay H Kramer; Xi Chen; Joanna J Chmielinska; Christopher F Spurney; William B Weglicki Journal: Am J Physiol Regul Integr Comp Physiol Date: 2013-09-18 Impact factor: 3.619
Authors: Heather M Dehlin; Edward J Manteufel; Andrew L Monroe; Michael H Reimer; Scott P Levick Journal: Int J Cardiol Date: 2013-07-29 Impact factor: 4.164